He now cites roles in The Da Vinci Code and Oscar-winning movies A Beautiful Mind, where he met his wife Jennifer Connelly, and Master And Commander among his impressive resume.
But his latest role has proved his most daunting yet.
In Creation, Bettany plays the revolutionary scientist Charles Darwin, the author of arguably the most explosive book in history, On the Origin of Species.
Published 150 years ago, the book was a culmination of more than 20 years of research inspired by his travels as a young man.
In the work, he revealed a scientific explanation for the diversity of species, including the evolution of man, and forever changed the way we view our place in the world.
Creation is based upon 'Annie's Box', a book written by Darwin's great-great grandson, Randal Keynes. In it, we see Darwin as a young and vibrant family man - albeit one whose mental and physical health gradually buckles under the weight of guilt and grief for a lost child, his beloved ten-year-old daughter, Annie.
A man torn between his love for his deeply religious wife and his own growing belief in a world where God has no place, Darwin even wrote that by effectively 'killing' God he felt like he was "confessing a murder".
So there's much to talk about as I prepare to interview the 38-year-old actor at the Royal Institute of Great Britain.
Opening a door, I step into a grand but dimly-lit room. There is shelf upon shelf of books but no sign of Mr Bettany, so I take a seat and only then do I notice the soles of two feet hanging off the end of a line of chairs.
"Um... Paul," the PR says gently and a rather tired and bewildered looking Bettany pops his head up.
It turns out Bettany is feeling rather poorly and admits he only got an hour's sleep the night before but ever the professional, he takes his seat under the spotlight and ploughs on with the interview.
His blue eyes may look slightly glassy but even in this exhausted state, Bettany still makes a striking figure. Tall and slim, his hair is shaved for a film role but it only maximises his razor-sharp cheekbones.
"Darwin's a bit of a hero of mine. I think he was an extraordinarily brave human being," he says in quiet but well-spoken words. "I like the idea of a person who is a social conservative having this revolutionary idea."
He felt particularly close to his character while filming at Darwin's actual home, Down House in Kent: "It was beautiful. I am not particularly sentimental but I was really moved. I found it extraordinary to walk that walk where a great deal of his thinking was done. You felt a bit like a ghost for a second."
For director Jon Amiel there was never any question as to who would play Darwin. Jon has said: "Paul's physically the most like Charles Darwin that you could possibly imagine but above all else he is a very, very intelligent man and brings to the role an effortless, piercing, luminous intelligence."
Bettany's far too modest to comment on such praise but he's willing to acknowledge the physical similarities although he adds, "Darwin had a much rounder face than me though, so I put on about 40 pounds through eating cheese sandwiches. It was awesome."
As for acquiring Darwin's receding hairline in the make-up chair, he admits: "That was less fun.
"You know, if I think I were going bald, I wouldn't have a problem with it but when you've done it to yourself and people go, 'Oh you're losing your hair,' you're like, 'No I'm not' and you begin to protest too much," he adds quietly and tries to raise a smile.
When Bettany received the script for Creation, he says, "I thought it was beautiful, one of the best scripts I've ever read. It's a story about a marriage in crisis and the loss of a child. It's compelling enough even if it wasn't about Darwin."
Creation is a tale of great love. Married to his wife Emma for 44 years, together they had ten children, although only seven survived to adulthood.
"We wanted to make the science clear but the film doesn't deal with the political fall-out about his ideas, not really," says Bettany. "It deals with the domestic fall-out of his ideas.
"Charles and Emma were so in love with each other, they just entirely adored each other, but had this incredibly alienating experience at a time when she was being drawn into religion and he was being pulled apart.
"Their child Annie had died and he and his wife were distraught and in some respects he was about to rob the one balm she had for that pain," says Bettany. "That must have been really difficult. She was a real believer, it was the backbone of her world."
It made absolute sense that Bettany's wife, Oscar-winning actress, Jennifer Connelly played the part of Emma. "I showed her the script and said 'I think this will be a great part for you' and it was that simple," says Bettany, taking a sip of orange juice.
Had they been actively looking to work on a project together? "Only in that I think she's a great actress and think it would be a shame not to work with her," he says. "I mean she's my wife, it wasn't like we were actively seeking something."
He admits they ended up "talking shop" sometimes but says: "More of the emotional stuff comes home with you but you've got each other to be cuddly with and look after each other."
He and Jennifer now live in New York with their son, Stellan, 6 and Jennifer's son from a previous relationship, Kai, 12.
"You know, work-wise it doesn't really matter where we live. I'm in a lucky position that it just doesn't matter for me anymore," he says. "Jennifer has lots of relatives there and I love it in New York. We also have a place in the country, which is fantastic."
But he adds with one last valiant effort, "It took me three years to realise '**** I'm not going home, I'd better get some American mates!'"
And with that it's time to leave Bettany to enjoy what rest he can, before the next interview begins.
Extra time - Paul Bettany
:: He was born on May 27, 1971, in Harlesden, near London.
:: He studied at The Drama Centre before starting his career with roles in television, including Killer Net and a Lynda La Plante thriller.
:: He plays the guitar and before he made it big, used to busk on Westminster Bridge.
:: He gave up smoking in 2005 after seeing his two-year old son imitate him with a pen.
:: He was nominated for London Film Critics Circle Best Actor award for his role as a psycho gangster in Gangster No.1.